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(American Journal of Pathology. 2004;164:2003-2012.)
© 2004 American Society for Investigative Pathology

Dynamic Regulation of Estrogen Receptor-ß Expression by DNA Methylation During Prostate Cancer Development and Metastasis

Xuegong Zhu*, Irwin Leav{dagger}{ddagger}, Yuet-kin Leung*, Mengchu Wu*, Qin Liu§, Ying Gao*, John E. McNeal and Shuk-Mei Ho*

From the Departments of Surgery,*Pathology,{dagger}and Cancer Biology,§University of Massachusetts Medical School, Worcester, Massachusetts; the Department of Pathology,{ddagger}Tufts School of Veterinary Medicine, Grafton, Massachusetts; and the Department of Urology,Stanford University Medical Center, Stanford, California

Estrogen receptor (ER)-ß is thought to exert anti-proliferative effects in the normal prostate but supports prostate cancer (PCa) cell survival. We previously reported that the receptor’s expression declined as PCa developed in the gland but reappeared in lymph node and bone metastases. To investigate whether hypermethylation was the underlying mechanism for these phenomena, we first identified two CpG islands (CGIs) encompassing 41 CpG dinucleotides, located separately in the untranslated exon 0N and the promoter region of ER-ß. Using immunostained, laser capture-microdissected samples from 56 clinical specimens, we demonstrated an inverse relationship exists between the extent of ER-ß CGI methylation and receptor expression in normal, hyperplastic, premalignant, and malignant foci of the prostate and in lymph node and bone metastases. Treatment of PCa cell lines (LNCaP and DU145), that express little ER-ß mRNA, with a demethylating agent increased levels of receptor expression thus corroborating our in vivo findings that methylation is involved in ER-ß silencing. Methylation centers in the promoter region and exon 0N were identified by hierarchical cluster analysis of bisulfite sequencing data obtained from 710 alleles. Methylation at these centers was insignificant in normal epithelium, reached 80 to 90% in grade 4/5 PCa, but declined to less than 20% in bone metastases. In addition, progressive methylation spreading from the exonic CGI to the promoter CGI, which correlated with loss of ER-ß expression, was detected in microdissected samples and in cell cultures. Using a new class of methylated oligonucleotides that mediate sequence-specific methylation in cellulo, we demonstrated that methylation of the promoter CGI, but not the exonic CGIs, led to transcriptional inactivation of ER-ß. Our results present the first evidence that epigenetic regulation of ER-ß is a reversible and tumor stage-specific process and that gene silencing via methylated oligonucleotides may have therapeutic potential in the treatment of advanced PCa.




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